Novel compound inhibiting BRD protein

Abstract

To provide a new carboxamide derivative possessing BRD protein inhibitory capability and a pharmaceutical composition comprising the carboxamide derivative for preventing or treating ophthalmic diseases.SOLUTION: The present invention provides a compound of formula (I), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof. (In the formula, A and B are each independently O, N, or S, and C and D are hydrogen, C1-6 alkyl, or the like.)SELECTED DRAWING: Figure 1

Description

[Technical Field]

[0001] The present invention relates to novel carboxamide derivatives that exhibit BRD protein inhibitory activity and compositions containing the same as active ingredients for the prevention and treatment of ophthalmic diseases. Specifically, the novel carboxamide derivatives of the present invention have BRD inhibitory activity, suppress inflammatory responses, and inhibit retinal degeneration, thereby providing pharmaceutical compositions for the prevention and treatment of various ophthalmic diseases such as diabetic retinopathy, wet and dry macular degeneration, glaucoma, and uveitis. [Background technology]

[0002] Histone post-translational modifications (PTMs) are involved in the regulation of gene expression and chromatin organization in eukaryotic cells. Histone acetylation at specific lysine residues is a PTM regulated by histone acetylases and histone deacetylases. Histone acetylation regulates gene expression by recruiting protein complexes, where highly conserved proteins called bromodomains directly bind to acetylated lysines in histones and other proteins. There are over 60 bromodomain-containing proteins in the human genome.

[0003] The BRD proteins include BRD2, BRD3, BRD4, and BRDT, and except for BRDT, which is localized in the testis, the remaining proteins are widely expressed in various tissues. The BRD protein family has also been reported to be associated with various diseases, including cancer, metabolic disorders, and inflammation.

[0004] For example, oncogenic fusions of BRD4 or BRD3 and the nuclear testicular protein (NUT) gene, caused by chromosomal translocations, result in an aggressive cancer termed NUT midline carcinoma (French et al., J Clin Oncol, 22 (2004), 4135-9; French et al., J Clin Pathol, 63 (2008), 492-6). The BRD3 / 4 bromodomain is conserved in these fusion proteins, and knockdown or the selective BRD protein inhibitor JQ1 causes the death of these cancer cells both in vitro and in animal tumor models (Filippakopoulos et al., Nature, 468 (2010), 1067-73). JQ1 and other selective BRD inhibitors bind to BRD and prevent acetyl-lysine binding, which is known to prevent BRD proteins from interacting with chromatin and thereby regulating transcription.

[0005] BRD4 was identified as a target in acute myeloid leukemia (AML) by RNAi screening (Zuber et al., Nature, 478 (2011), 524-8). These findings were verified in vitro and in vivo using the BRD inhibitors JQ1 and I-BET151 (Dawson et al., Nature, 478 (2011), 529-33). It is also known that BRD inhibitors have broad anticancer activity in acute leukemia, multiple myeloma, and other hematological malignancies. In various cancer models, acute downregulation of the oncogenic transcription factor Myc was observed upon BRD inhibition (Delmore et al., Cell, 146 (2011), 904-17; Mertz et al., Proc Natl Acad Sci USA, 108 (2011), 16669-74). Recent studies suggest that BRD inhibitors may have potential applications in other cancers, such as lung and brain cancer.

[0006] Another BRD inhibitor, I-BET762, closely related to JQ1 in chemical structure and BRD binding mode, has been reported to regulate the expression of key inflammatory genes and protect against endotoxic shock and bacterial-induced sepsis in mouse models (Nicodeme et al., Nature, 468 (2010), 1119-23). ​​These results have also been used to support the clinical evaluation of the BRD inhibitor RVX-208 in clinical trials in patients with atherosclerosis, coronary artery disease, hemostatic disorders, diabetes, and other cardiovascular diseases (McNeill, Curr Opin Investig Drugs, 3 (2010), 357-64 and www.clinicaltrials.gov).

[0007] Both RVX-208 and I-BET762 have been shown to upregulate apolipoprotein AI, which is important in reducing tissue cholesterol levels. Furthermore, BRD proteins are involved in the regulation of the proliferation and transcription of several viruses, suggesting that BRD inhibitors may have antiviral activity (Weidner-Glunde, Frontiers in Bioscience 15 (2010), 537-549).

[0008] Under these circumstances, the present inventors have confirmed that a novel BRD-inhibiting small molecule synthetic substance that exhibits excellent inhibitory activity against the BRD protein, an epigenetic identifier, has excellent retinal degeneration inhibitory activity, which can prevent and treat eye diseases caused by retinal degeneration, and have thereby completed the present invention.

[0009] Although several bromodomain inhibitors are known in clinical and preclinical studies, there is a pressing need for the development of novel bromodomain inhibitors that can resolve the problems of disease recurrence and resistance to therapeutic agents and have reduced side effects.

[0010] Redox reactions, on the other hand, are present in numerous physiological processes. While molecular oxygen is necessary for life, it can also generate reactive molecules that lead to disease. Other reactive chemical species, including free radicals, can also cause pathological conditions. Reactive oxygen species (ROS) have long been known to cause aerobic metabolism associated with tissue damage. ROS and the more recently discovered reactive nitrogen species (RNS) act as messengers in cell signaling, similar to hormones, and can cause chemical modifications of enzymes, resulting in changes in oxidant levels.

[0011] Among the 20 essential amino acids, cysteine, methionine, tyrosine, and tryptophan are particularly susceptible to oxidation. Therefore, when these proteinaceous substances are metabolized in the human body, they undergo various modifications, such as metal binding, disulfide bond formation, methylation, and acetylation.

[0012] While research into cellular signaling mechanisms has focused on phosphorylation to date, the present invention was accomplished by applying redox chemistry techniques that take into account redox regulation mechanisms such as oxidation and S-nitrosylation, which are mediated by the "redox state," to address diseases caused by oxidative and nitrate stress. Specifically, the present inventors have researched and developed novel bromodomain inhibitors that take into account the redox state, based on the fact that the degree of binding between signaling substances differs depending on the redox state when BRD inhibitors recognize lysine residues in histone proteins.

[0013] The eye is composed of the outer, middle, inner, and refractive media. The outer consists of the cornea, the anterior surface covering the black part of the eye, and the sclera, which connects to the posterior surface. The middle consists of the iris, ciliary body, and choroid. The inner consists of the retina. The lens, vitreous, and aqueous humor are all refractive media. Functional impairment or loss of eyes is one of the major factors that significantly reduce quality of life. Maintaining eye health is becoming increasingly important because various factors, such as aging, disease, and vision, can adversely affect eye health. Ocular diseases include retinal diseases, including retinal degenerative diseases and glaucoma, cataracts, and corneal epithelial damage or wounds.

[0014] Currently, known treatments for these eye diseases include laser therapy, photocoagulation, cryocoagulation, and photodynamic therapy. All of these treatments are surgical, while drug-based treatments are still in the development stage. Surgical treatments have the disadvantage of not being applicable to all patients, and they have low success rates and are expensive, causing social and economic problems. Unfortunately, most patients who cannot undergo surgery are currently without specific treatments, resulting in blindness. As human lifespans continue to increase, the incidence of these eye diseases continues to increase, creating an urgent need to develop appropriate treatments.

[0015] Therapeutic agents for eye diseases currently under development mainly consist of steroids, matrix metalloproteinase (MMP) inhibitors, angiogenesis inhibitors, antibodies against angiogenic growth factors, and the like.

[0016] The macula is a nerve tissue located in the center of the retina. Most of the photoreceptor cells are concentrated here, where the image of an object is formed and is primarily responsible for central vision. Macular degeneration is an eye disease that usually progresses with age, causing visual impairment due to degeneration of the macula. In the early stages of the disease, vision becomes blurred and close vision becomes distorted, but it is one of the eye diseases that is difficult to treat, as it can later cause blindness.

[0017] Age-related macular degeneration (AMD) is now known to be the most common cause of blindness among the elderly, affecting approximately 30 million people worldwide, with approximately 500,000 patients losing their sight each year. In Korea, AMD is one of the three major causes of blindness, along with glaucoma and diabetic retinopathy, and its prevalence is steadily increasing as the elderly population grows. The age at which the disease develops is also trending downward from the 60s to middle-aged people in their 40s and 50s.

[0018] Age-related macular degeneration is broadly classified into two types: exudative (wet) macular degeneration and atrophic (dry) macular degeneration. The exudative type accounts for approximately 10% of age-related macular degeneration cases, and is known to be responsible for 70-90% of blindness due to age-related macular degeneration, which is accompanied by fundus findings such as choroidal neovascularization, retinal pigment epithelial detachment, sensory retinal detachment, and retinal pigment epithelial tears.

[0019] Recently, intravitreal injection of anti-vascular endothelial growth factor (AEGF), a treatment for exudative age-related macular degeneration (WMD), has improved patient vision and prognosis. However, this treatment is expensive and has a short half-life, which requires repeated injections every month. Furthermore, the direct delivery of the drug into the vitreous cavity increases the risk of complications such as cataracts, endophthalmitis, vitreous hemorrhage, and retinal detachment. Therefore, there is a pressing need to develop a treatment that addresses these side effects and is more convenient for patients.

[0020] Glaucoma is a disease that causes the loss of retinal ganglion cells and is closely related to retinal disease.

[0021] Retinal degenerative diseases are known to be progressive diseases caused by various environmental factors, such as genetic or oxidative stress, which simultaneously cause the degeneration of photoreceptor cells and result in vision loss. Patients often complain of a narrowing of peripheral vision, similar to night blindness, from the early stages of the disease, while central vision is relatively well preserved. However, vision declines in the late stages. Glaucoma is a diverse group of diseases that exhibits a variety of clinical and histopathological findings, and symptoms include changes in the optic disc, damage to retinal ganglion cells, and resulting visual field defects.

[0022] The retina is the innermost tissue of the eyeball and belongs to the central nervous system. Retinal degeneration is associated with retinal diseases such as age-related macular degeneration and retinitis pigmentosa, and is a pathological phenomenon that ultimately leads to blindness due to the death of photoreceptor cells, exhibiting the characteristics of neurodegenerative diseases. Unlike other neurodegenerative diseases, there are currently no methods that can suppress retinal degeneration, and therefore retinal diseases associated with retinal degeneration can be said to be intractable diseases. In recent years, it has been reported that inflammatory responses are extremely important in retinal degeneration, and that retinal degeneration can be suppressed by controlling such neuroinflammation.

[0023] Many diseases, including neurodegenerative diseases, are associated with epigenetic changes, and recent efforts have aimed to prevent and treat these diseases by regulating these changes. For example, JQ, a broad-spectrum BRD protein inhibitor, has demonstrated therapeutic potential in a mouse model of retinitis pigmentosa through microglial cell activation (Zhao et al., 2017, Photoreceptor protection via blockade of BRD epigenetic readers in a murine model of inherited retinal degeneration. Journal of Neuroinflammation (2017) 14:14, 1-15).

[0024] Under these circumstances, the present inventors have confirmed that novel carboxamide derivatives that exhibit excellent inhibitory activity against BRD protein, an epigenetic identifier, have excellent retinal degeneration inhibitory activity, which can prevent and treat eye diseases caused by retinal degeneration, and have thereby completed the present invention. [Prior art documents] [Non-patent literature]

[0025] [Non-Patent Document 1] Zhao et al, 2017, Photoreceptor protection via blockade of BRD epigenetic readers in a murine model of inherited retinal degeneratio.Journal of Neuroinflammation(2017)14:14,1-15 Summary of the Invention [Problem to be solved by the invention]

[0026] The present invention provides novel carboxamide derivatives that have the ability to inhibit BRD protein, and also provides compositions for the prevention or treatment of ophthalmic diseases such as diabetic retinopathy, glaucoma, uveitis, wet and dry macular degeneration, and age-related macular degeneration, utilizing the effect of the novel low molecular weight compounds of the present invention, which suppress retinal degeneration, such as reducing inflammation, through epigenetic changes. [Means for solving the problem]

[0027] The present invention provides compounds of formula (I), solvates, stereoisomers, or pharmaceutically acceptable salts thereof:

[0028] [ka] In the above formula, A and B are each independently any one selected from the group consisting of oxygen, nitrogen, and sulfur, and when at least one of A and B is nitrogen, a hydrogen atom bonded to the nitrogen atom is substituted with an alkyl group; C is hydrogen, C 1-6 is any one selected from the group consisting of alkyl and carbonyl, D is hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NH(C 3-6 cycloalkyl), cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0029] The present invention provides compounds of formula (II), solvates, stereoisomers, or pharmaceutically acceptable salts thereof:

[0030] [ka] In the above formula, A and B are each independently any one selected from the group consisting of oxygen, nitrogen, and sulfur, and when at least one of A and B is nitrogen, a hydrogen atom bonded to the nitrogen atom is substituted with an alkyl group; C is hydrogen or C 1-6 is alkyl, D is hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of hydrogen, —OH, ═O, —C 1-6 Alkyl, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C 1-6may be substituted with one or more substituents selected from the group consisting of alkylC(=O)N(Ra)(Rb) and benzyl in which one or more of hydrogen or carbon is substituted with halogen; the heterocycloalkyl includes one or more selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, and piperazinonyl; The Ra and Rb are each independently H or C 1-6 It is alkyl.

[0031] The present invention also provides a pharmaceutical composition for preventing or treating ophthalmic diseases, which comprises the compound, solvate, stereoisomer, or a pharmaceutically acceptable salt thereof as an active ingredient.

[0032] Ophthalmological diseases of the present invention include, but are not limited to, endophthalmitis, keratitis, conjunctivitis, keratoconjunctivitis, uveitis, blepharitis, scleritis, iritis, glaucoma, retinal degeneration, retinitis pigmentosa, retinal detachment, retinal pigment epithelial detachment, retinal breaks, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber's hereditary optic neuropathy, corneal neovascularization, retinal and choroidal neovascularization, wet and dry macular degeneration, or age-related macular degeneration.

[0033] Preferably, the ophthalmic disease of the present invention may be diabetic retinopathy, glaucoma, uveitis, wet and dry macular degeneration, or age-related macular degeneration. [Effects of the Invention]

[0034] The compounds of formula (I) or formula (II), solvates, stereoisomers, or pharmaceutically acceptable salts thereof of the present invention alleviate inflammatory responses induced by retinal degeneration through epigenetic inhibition of BRD protein, thereby effectively inhibiting retinal degeneration. This ability to inhibit retinal degeneration can also be utilized in the treatment of retinal degeneration and other central nervous system diseases by controlling neuroinflammation. Therefore, the compounds of formula (I) or formula (II), solvates, stereoisomers, or pharmaceutically acceptable salts thereof can be useful for the prevention or treatment of various eye diseases, such as diabetic retinopathy, glaucoma, uveitis, wet and dry macular degeneration, and age-related macular degeneration. [Brief explanation of the drawings]

[0035] [Figure 1] 1 shows the results of OCT imaging for the administration group of Example 21. [Figure 2] 1 shows the results of OCT imaging for the administration group of Example 25. [Figure 3] 1 shows the results of OCT imaging for the administration group of Comparative Example 4. [Figure 4] 1 shows the results of FFA imaging for the administration group of Example 21. [Figure 5] 1 shows the results of FFA imaging for the administration group of Example 25. [Figure 6] 1 shows the results of FFA imaging for the administration group of Comparative Example 4. DETAILED DESCRIPTION OF THE INVENTION

[0036] Various embodiments of the present invention will be described below with reference to the accompanying drawings. It should be understood that the present invention is not limited to specific embodiments, but includes various modifications, equivalents, and / or alternatives of the embodiments of the present invention. In connection with the description of the drawings, like reference numerals may be used for similar components.

[0037] In this specification, the terms "have," "can have," "include," or "can include" indicate the presence of a given feature (e.g., a value, function, operation, or component such as a part) and do not exclude the presence of additional features.

[0038] As used herein, phrases such as "A or B," "at least one of A and / or B," or "one or more of A and / or B" include all possible combinations of the items listed together. For example, "A or B," "at least one of A and B," or "at least one of A or B" can refer to any of the following: (1) including at least one A; (2) including at least one B; or (3) including at least one A and at least one B.

[0039] As used herein, the expression "configured to" can be used interchangeably with, for example, "suitable for," "having the capacity to," "designed to," "adapted to," "made to," or "capable of," depending on the context. The term "configured to" does not necessarily mean only "specifically designed to."

[0040] The terms used in this specification are merely used to describe particular embodiments and may not be intended to limit the scope of other embodiments. A singular expression may include a plural expression unless the context clearly dictates otherwise. Terms used herein, including technical or scientific terms, may have the same meaning as commonly understood by a person of ordinary skill in the art described herein. Terms used in this specification that are defined in a general dictionary may be interpreted in the same or similar meaning as the meaning they have in the context of the relevant art, and unless expressly defined in this specification, they should not be interpreted in an idealized or overly formal sense. In some cases, even terms defined in this specification should not be interpreted to exclude embodiments of this specification.

[0041] The embodiments disclosed in this specification are presented for the purpose of explaining and understanding the disclosed technical content, and are not intended to limit the scope of the present invention. Therefore, the scope of the specification should be interpreted as including any modifications or various other embodiments based on the technical concept of the present invention.

[0042] In the following, preferred embodiments of the present invention will be described in detail. Prior to this, the terms and words used in the specification and claims should not be interpreted in a limited manner based on their ordinary or dictionary meanings, but should be interpreted in a manner that is consistent with the technical concept of the present invention, based on the principle that the inventor can appropriately define the concept of the term in order to best describe his / her invention.

[0043] Therefore, it should be understood that the configurations of the embodiments described in this specification are merely some of the most preferred embodiments of the present invention and do not fully represent the technical ideas of the present invention, and that there may be various equivalents and modifications that can be substituted for them at the time of filing this application.

[0044] Throughout the specification, when a part "comprises" a certain element, this does not mean that it excludes other elements, but that it may further include other elements, unless otherwise specified to the contrary.

[0045] The present invention will be specifically described below.

[0046] The present invention relates to novel compounds represented by the following formula (I) or formula (II), and more specifically to novel compounds having inhibitory activity against BRD protein and pharmaceutical compositions containing the same for preventing or treating BRD protein-related diseases.

[0047] [ka]

[0048] [ka] Unless otherwise specified, terms used in describing and claiming the present invention have the meanings disclosed below.

[0049] In accordance with the convention used in the art, "

[0050] [ka] " is used to indicate that a residue or substituent "R" is attached to the backbone structure.

[0051] "Alkyl" refers to a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, and includes saturated aliphatic groups that can be linear, branched, or cyclic, or combinations thereof. For example, an alkyl group can have from 1 to 20 carbon atoms (i.e., C1-C 20 alkyl), 1 to 10 carbon atoms (i.e., C1-C 10The alkyl group may have 1 to 6 carbon atoms (i.e., C1-C6 alkyl). Unless otherwise specified, in preferred embodiments, alkyl refers to C1-C6 alkyl. Examples of suitable alkyl groups include methyl (Me, -CH3), ethyl (Et, -CH2CH3), 1-propyl (n-Pr, n-propyl, -CH2CH2CH3), 2-propyl (i-Pr, i-propyl, -CH(CH3)2), 1-butyl (n-Bu, n-butyl, -CH2CH2CH2CH3), 2-methyl-1-propyl (i-Bu, i-butyl, -CH2CH(CH3)2), 2-butyl (s-Bu, s-butyl, -CH(CH3) CH2CH3), 2-methyl-2-propyl (t-Bu, t-butyl, -C(CH3)3), 1-pentyl (n-pentyl, -CH2CH2CH2CH2CH3), 2-pentyl (-CH(CH3)CH2CH2CH3), 3-pentyl (-CH(CH2CH3)2), 2-methyl-2-butyl (-C(CH3)2CH2CH3), 3-methyl-2-butyl (-CH(CH3)CH(CH3)2), 3-methyl-1-butyl (-CH2CH2CH( CH3)2), 2-methyl-1-butyl (-CH2CH(CH3)CH2CH3), 1-hexyl (-CH2CH2CH2CH2CH2CH2CH3), 2-hexyl (-CH(CH3)CH2CH2CH2CH2CH3), 3-hexyl (-CH(CH2CH3)(CH2CH2CH3)), 2-methyl-2-pentyl (-C(CH3)2CH2CH2CH3), 3-methyl-2-pentyl (-CH(CH3)CH(CH3)CH2CH3), 4-methyl- Examples include, but are not limited to, 2-pentyl (-CH(CH3)CH2CH(CH3)2), 3-methyl-3-pentyl (-C(CH3)(CH2CH3)2), 2-methyl-3-pentyl (-CH(CH2CH3)CH(CH3)2), 2,3-dimethyl-2-butyl (-C(CH3)2CH(CH3)2), 3,3-dimethyl-2-butyl (-CH(CH3)C(CH3)3), and octyl (-(CH2)7CH3).

[0052] Furthermore, the term "alkyl," as used throughout the specification, examples, and claims, is intended to include all unsubstituted and substituted alkyl groups, the latter of which refers to alkyl residues having substituents replacing a hydrogen on one or more carbons of the hydrocarbon backbone, including haloalkyl groups such as trifluoromethyl and 2,2,2-trifluoroethyl.

[0053] The term “C x-y " or "C x -C y " when used with chemical residues such as acyl, acyloxy, alkyl, alkenyl, alkynyl, or alkoxy, is considered to include groups containing x to y carbons in the chain. CO alkyl indicates a hydrogen if the group is in a terminal position and a bond if it is internal. For example, a (C1-C6) alkyl group contains 1 to 6 carbon atoms in the chain.

[0054] "Alkoxy" refers to a group having the formula -O-alkyl, where an alkyl group, as defined above, is attached to the parent compound through an oxygen atom. The alkyl residue of the alkoxy group can be, for example, 1 to 20 carbon atoms (i.e., C1-C 20 alkoxy), 1 to 12 carbon atoms (i.e., C1-C 12 alkoxy), 1 to 10 carbon atoms (i.e., C1-C 10 The alkoxy group may have 1 to 6 carbon atoms (i.e., C1-C6 alkoxy). Examples of suitable alkoxy groups include, but are not limited to, methoxy (-O-CH3 or -OMe), ethoxy (-OCH2CH3 or -OEt), and t-butoxy (-OC(CH3)3 or -O-tBu).

[0055] "Alkenyl" refers to groups having primary, secondary, tertiary, and / or quaternary carbon atoms, including linear, branched, and cyclic groups, or combinations thereof, and having one or more areas of unsaturation, i.e., carbon-carbon sp 2A hydrocarbon having a double bond. For example, an alkenyl group is a group having 2 to 20 carbon atoms (i.e., C2-C 20 alkenyl), 2 to 12 carbon atoms (i.e., C2-C 12 alkenyl), 2 to 10 carbon atoms (i.e., C2-C 10 alkenyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkenyl). Examples of suitable alkenyl groups include, but are not limited to, vinyl (-CH=CH2), aryl (-CH2CH=CH2), cyclopentenyl (-C5H7), and 5-hexenyl (-CH2CH2CH2CH2CH=CH2).

[0056] "Alkynyl" refers to a hydrocarbon having primary, secondary, tertiary, and / or quaternary carbon atoms, including linear, branched, and cyclic groups, or combinations thereof, and having one or more carbon-carbon sp triple bonds. For example, an alkynyl group can be any group having 2 to 20 carbon atoms (i.e., C2-C 20 alkynyl), 2 to 12 carbon atoms (i.e., C2-C 12 alkynyl), 2 to 10 carbon atoms (i.e., C2-C 10 alkynyl), or 2 to 6 carbon atoms (i.e., C2-C6 alkynyl). Examples of suitable alkynyl groups include, but are not limited to, acetylenyl (-C≡CH) and propynyl (-CH2C≡CH).

[0057] As used herein, the term "aryl" includes substituted or unsubstituted monovalent or divalent aromatic hydrocarbon groups, which may be monocyclic, bicyclic, or polycyclic, in which each atom of the ring is carbon. Preferably, the aryl ring is a 6- to 20-membered, 6- to 14-membered, 6- to 10-membered, or more preferably, a 6-membered ring. An aryl group may also be a polycyclic ring system having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where one or more of the rings is aromatic, and the other cyclic rings may be, for example, cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocycloalkyl. Examples of aryl groups include benzene, naphthalene, phenanthrene, anthracene, indene, indane, phenol, aniline, and the like.

[0058] The term "carbocyclylalkyl," or "cycloalkylalkyl," or "(cycloalkyl)alkyl," as used herein, refers to an alkyl group substituted with a carbocyclyl group or a cycloalkyl group.

[0059] As used herein, the terms "carbocycle," "carbocyclyl," "carbocyclic," or "cycloalkyl" refer to a non-aromatic saturated or unsaturated, monovalent or divalent ring, which may be monocyclic, bicyclic, or polycyclic, and in which each atom of the ring is carbon. Cycloalkyl groups may have 3 to 7 carbon atoms as monocyclos, 7 to 12 carbon atoms as bicyclos, and up to about 20 carbon atoms as polycyclos. Monocyclic cycloalkyls have 3 to 7 ring atoms, more typically 5 or 6 ring atoms. Bicyclic cycloalkyls may have 7 to 12 ring atoms and may be fused, spirocyclic, or bridged ring systems. In exemplary cycloalkyl groups, the atoms may be arranged in a bicyclo[4,5], [5,5], [5,6], or [6,6] system. In certain embodiments, cycloalkyls contain 3 to 20 atoms, or 3 to 10 atoms, or more preferably 3 to 7 atoms. Examples of cycloalkyl include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, etc. Unless otherwise specified, cycloalkyl may be optionally substituted with one or more substituents described herein.

[0060] The terms "heterocyclylalkyl" and "heterocycloalkyl," as used herein, refer to an alkyl group substituted with a heterocycloalkyl group.

[0061] The terms "heterocyclyl," "heterocycle," "heterocyclic," and "heterocycloalkyl" refer to substituted or unsubstituted, monovalent or divalent, saturated or partially saturated non-aromatic ring structures, preferably 3- to 10-membered rings, more preferably 3- to 7-membered rings, whose ring structures contain one or more heteroatoms, preferably 1 to 4 heteroatoms, more preferably 1 to 2 heteroatoms. The terms "heterocyclyl," "heterocycle," "heterocyclic," and "heterocycloalkyl" also include polycyclic ring systems having two or more cyclic rings in which two or more carbons are common to two adjacent rings, where one or more of the rings is heterocyclic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Bicyclic and polycyclic heterocyclic ring systems may be fused, bridged, or spiro ring systems. Substituted heterocycles include heterocyclic rings substituted with any of the substituents disclosed herein, including, for example, a carbonyl group.

[0062] Heterocyclyl groups include, for example, piperidine, piperazine, pyrrolidine, morpholine, lactones, lactams, etc. Further exemplary heterocyclos include dihydropyridyl, dihydroindolyl, tetrahydropyridyl (piperidyl), tetrahydrothiophenyl, sulfur-oxidized tetrahydrothiophenyl, indolenyl, piperidinyl, 4-piperidinyl, pyrrolidinyl, 2-pyrrolidonyl, pyrrolinyl, tetrahydrofuranyl, tetrahydroquinolinyl, tetrahydroisoquinolinyl, decahydroquinolinyl, octahydroisoquinolinyl, 6H-1,2,5-thiadiazinyl, 2H,6H-1,5,2-dithiazinyl, pyranyl, chromenyl, xanthenyl, phenoxathiinyl, 2H-pyrrolyl, 3H-indolyl, 4H-xanthen ... Examples of quinuclidinyl include, but are not limited to, 4aH-carbazolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, 4aH-carbazolyl, carbazolyl, B-carbolinyl, phenanthridinyl, acridinyl, phenanthrolinyl, phenazinyl, phenothiazinyl, furazanyl, phenoxazinyl, isochromanyl, chromanyl, imidazolidinyl, imidazolinyl, pyrazolidinyl, pyrazolinyl, piperazinyl, methylpiperazinyl, quinuclidinyl, morpholinyl, and oxazolidinyl (each of which may be substituted or unsubstituted).

[0063] "Heteroaryl" refers to a substituted or unsubstituted monovalent or divalent aromatic group, monocyclic, bicyclic, or polycyclic, containing one or more heteroatoms in the ring. Non-limiting examples of suitable heteroatoms that may be contained in the aromatic ring include oxygen, sulfur, and nitrogen. In a polycyclic heteroaryl ring system, the ring system has two or more cyclic rings in which two or more carbons are common to two adjacent rings, and one or more of the rings is heteroaromatic; for example, the other cyclic rings may be cycloalkyl, cycloalkenyl, cycloalkynyl, aryl, heteroaryl, and / or heterocyclyl. Heterogroups include, for example, benzofuran, benzothiophene, pyrrole, furan, thiophene, imidazole, indole, isoindole, isoxazole, isothiazole, oxazole, thiazole, quinoline, isoquinoline, pyrazole, pyridine, pyrazine, pyridazine, pyrimidine, and the like (each of which may be substituted or unsubstituted).

[0064] As used herein, the terms "halo" and "halogen" refer to halogen and include chloro, fluoro, bromo, and iodo.

[0065] "Amino" refers to the group -NH2.

[0066] "Carboxy" refers to the radical --C(O)OH.

[0067] "Aldehyde" refers to the group --CHO.

[0068] The present invention relates to compounds of formula (I) below, solvates, stereoisomers, or pharmaceutically acceptable salts thereof:

[0069] [ka] In the above formula, A and B are each independently any one selected from the group consisting of oxygen, nitrogen, and sulfur, and when at least one of A and B is nitrogen, a hydrogen atom bonded to the nitrogen atom is substituted with an alkyl group; C is hydrogen, C 1-6 is any one selected from the group consisting of alkyl, alkoxy, and carbonyl; D is hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NH(C 3-6 cycloalkyl), cycloalkyl, heterocycloalkyl, aryl or heteroaryl.

[0070] Specifically, in the present invention, the —NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), -NH(C 3-6 The hydrogen-bonding moieties of cycloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are hydrogen, halogen, -OH, =O, -OC 1-6 Alkyl, -C 1-6 Alkyl, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C 1-6 AlkylC(=O)N(Ra)(Rb), -C3H4C(=O)N(Ra)(Rb), -C≡CH, -C 3-6 Cycloalkyl, -N(C 1-6 Alkyl)(C 1-6 alkyl), -SO2(C 1-6 alkyl), phenyl, phenyl in which one or more of hydrogen or carbon is substituted with halogen, methylpiperazinyl, any of hydrogen is C 1-6It may be substituted with one or more substituents selected from the group consisting of alkyl-substituted pyrazolyl, pyrrolidonyl in which any of the hydrogen atoms is substituted with a halogenated phenyl, methylpyrrolidonyl in which any of the hydrogen atoms is substituted with a halogenated phenyl, benzyl, and benzyl in which any one or more of hydrogen atoms or carbon atoms are substituted with nitrogen atoms and any one or more of hydrogen atoms or carbon atoms are substituted with halogen atoms, and the Ra and Rb are each independently selected from H, C 1-6 Alkyl, C 3-6 It may be cycloalkyl or benzyl.

[0071] More specifically, in the present invention, the heterocycloalkyl of D may include one or more selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, and piperazinonyl.

[0072] More specifically, in the present invention, C may be either methyl or carbonyl.

[0073] The present invention also relates to a compound of the following formula (II), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof:

[0074] [ka] In the above formula, A and B are each independently any one selected from the group consisting of oxygen, nitrogen, and sulfur, and when at least one of A and B is nitrogen, a hydrogen atom bonded to the nitrogen atom is substituted with an alkyl group; C is hydrogen or C 1-6 is alkyl, D is hydrogen, C 1-6 Alkyl, -NH2, -NH(C 1-6 alkyl), -N(C 1-6 Alkyl)(C 1-6 alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of hydrogen, —OH, ═O, —C 1-6 Alkyl, -C(=O)Ra, -C(=O)N(Ra)(Rb), -C 1-6 may be substituted with one or more substituents selected from the group consisting of alkylC(=O)N(Ra)(Rb) and benzyl in which one or more of hydrogen or carbon is substituted with halogen; the heterocycloalkyl includes one or more selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, and piperazinonyl; The Ra and Rb are each independently H or C 1-6 It is alkyl.

[0075] Specifically, in the present invention, C may be methyl.

[0076] The present invention also relates to a compound of formula (I), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds represented by the chemical formulae in Tables 1 to 6 below, but is not limited thereto.

[0077] [Table 1]

[0078] [Table 2]

[0079] [Table 3]

[0080] [Table 4]

[0081] [Table 5]

[0082] [Table 6] The present invention also relates to a compound of formula (II), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, which is selected from the group consisting of compounds represented by the chemical formulas in Table 7 below, but is not limited thereto.

[0083] [Table 7] The present invention also relates to a pharmaceutical composition for preventing or treating an ophthalmic disease, which comprises, as an active ingredient, the compound of formula (I) or formula (II), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof.

[0084] The ophthalmological diseases include, but are not limited to, endophthalmitis, keratitis, conjunctivitis, keratoconjunctivitis, uveitis, blepharitis, scleritis, iritis, glaucoma, retinal degeneration, retinitis pigmentosa, retinal detachment, retinal pigment epithelial detachment, retinal breaks, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber's hereditary optic neuropathy, corneal neovascularization, retinal-choroidal neovascularization, wet and dry macular degeneration, and age-related macular degeneration. Preferably, the target substance is diabetic retinopathy, glaucoma, uveitis, wet and dry macular degeneration, or age-related macular degeneration.

[0085] As used herein, the term "treating" or "treatment" refers to inhibiting a disease, e.g., inhibiting a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, i.e., preventing further occurrence of the pathology and / or symptoms, or ameliorating a disease, e.g., ameliorating a disease, condition, or disorder in an individual experiencing or exhibiting the pathology or symptoms of the disease, condition, or disorder, i.e., reversing the pathology and / or symptoms, e.g., reducing disease severity.

[0086] As used herein, the term "prevent" or "prevention" refers to preventing a disease, for example, preventing a disease, condition, or disorder in an individual who may be prone to the disease, condition, or disorder, but who has not yet experienced or exhibited pathology or symptoms of the disease.

[0087] In one embodiment, the pharmaceutical composition may contain a conventional pharmaceutically acceptable carrier, excipient, or additive, and may be formulated according to a conventional method into various oral dosage forms such as tablets, pills, powders, capsules, syrups, emulsions, and microemulsions, or parenteral dosage forms such as intramuscular, intravenous, or subcutaneous administration.

[0088] When the pharmaceutical composition is prepared in the form of an oral dosage form, examples of the additives or carriers used include cellulose, calcium silicate, corn starch, lactose, sucrose, dextrose, calcium phosphate, stearic acid, magnesium stearate, calcium stearate, gelatin, talc, surfactants, suspending agents, emulsifiers, diluents, etc. When the pharmaceutical composition of the present invention is prepared in the form of an injection, examples of the additives or carriers include water, saline, aqueous glucose solution, aqueous saccharide solution, alcohol, glycol, ether (e.g., polyethylene glycol 400), oil, fatty acid, fatty acid ester, glyceride, surfactant, suspending agent, emulsifier, etc.

[0089] The dosage of the pharmaceutical composition is an amount effective for the treatment or prevention of an individual or patient and can be administered orally or parenterally depending on the purpose. For oral administration, the active ingredient is administered in an amount of 3 to 20 mg, more specifically 5 to 10 mg, per kg of body weight per day. For parenteral administration, the active ingredient is administered in an amount of 3 to 20 mg, more specifically 5 to 10 mg, per kg of body weight per day. The dosage can be administered once or several times in divided doses. The dosage for a particular individual or patient should be determined in light of various relevant factors, such as the patient's weight, age, sex, health condition, diet, administration time, administration method, and disease severity. It should be understood that this dosage can be appropriately adjusted by a specialist, and the dosage does not limit the scope of the present invention in any way. A physician or veterinarian with ordinary skill in the relevant art can easily determine and prescribe the effective amount of the pharmaceutical composition required. For example, a physician or veterinarian can start the dosage of the compound of the present invention used in the pharmaceutical composition at a level lower than that required to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.

[0090] Specifically, the compound of formula (I) or formula (II) of the present invention, solvates, stereoisomers, or pharmaceutically acceptable salts thereof can inhibit ocular neovascularization and prevent or treat macular degeneration, including, but not limited to, wet and dry macular degeneration and age-related macular degeneration, and can also act on various eye diseases such as diabetic retinopathy, glaucoma, and uveitis.

[0091] Furthermore, the experimental results of the examples show that the novel compounds of the present invention can alleviate inflammation caused by various epigenetic changes, such as inhibiting BRD protein, and inhibit retinal degeneration, and exhibit excellent therapeutic effects on various eye diseases such as diabetic retinopathy, glaucoma, uveitis, age-related macular degeneration, and wet and dry macular degeneration.

[0092] The present invention relates to pharmaceutical compositions containing novel compounds for the prevention or treatment of various eye diseases such as diabetic retinopathy, glaucoma, uveitis, wet and dry macular degeneration, and age-related macular degeneration.

[0093] The present invention will be described in detail below with reference to examples to aid in understanding the present invention. However, the following examples are merely illustrative of the contents of the present invention, and the scope of the present invention is not limited to the following examples. The examples of the present invention are provided to more completely explain the present invention to those skilled in the art. [Example]

[0094] [Manufacturing example] The structures of the compounds of the present invention were confirmed by nuclear magnetic resonance (NMR) and mass spectrometry (MS). NMR was measured on a Bruker Avance-400 or Bruker Avance 300 instrument. The solvents used for the measurements were deuterated dimethyl sulfoxide (DMSO-d), deuterated chloroform (CDCl), and deuterated methanol (CD3OD), and the internal standard was tetramethylsilane (TMS).

[0095] High performance liquid chromatography (HPLC) was performed by flash chromatography or column chromatography.

[0096] Thin-layer chromatography (TLC) was performed on silica gel plates. 1000 mesh silica gel was used for thin-layer chromatography. The size of the silica gel plates used for TLC was 20-25 μm, and the size of the silica gel plates used for product purification was 40-45 μm.

[0097] Visualization was performed using ultraviolet light, iodine, and potassium permanganate in water.

[0098] The known starting materials of the present invention can be prepared by conventional synthetic methods in the art or can be purchased from Sigma-Aldrich, TCI, Wako, Kanto, Fluorchem, Acros, Alfa, Fluka, Combi-Blocks, Dae-Jung, etc.

[0099] Compounds 1 to 42 of the present invention were prepared according to the following Preparations and Examples.

[0100] <Production Example 1> Production of 5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde

[0101] [ka] <Production Example 1-1> Production of 5-(2-bromophenyl)furan-2-carbaldehyde 2-Bromoaniline (3.36 g, 35.0 mmol) was dissolved in 2N aqueous HCl (50 mL), and cuprous iodide (666 mg, 3.50 mmol) was added dropwise. The mixture was stirred at 0°C. Sodium nitrite (4.83 g, 70.0 mmol) was slowly added dropwise at the same temperature. After stirring for 1 hour, furan-2-carbaldehyde (5.04 g, 52.5 mmol) was added and the mixture was stirred at room temperature for 12 hours. Ethyl acetate (200 mL) was added, and the mixture was washed with water (200 mL, twice), dried over anhydrous magnesium sulfate, and then filtered. The filtrate was distilled under reduced pressure. Separation by silica gel column chromatography afforded the following compound (2.00 g, 7.96 mmol).

[0102] 1 H-NMR (400MHz, DMSO-d6)δ 9.68(s, 1H), 7.66(m, 2H), 7.73(d, 1H), 7.52(t, 1H), 7.44(t, 1H), 7.32(s, 1H) <Production Example 1-2> Production of 5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde The compound obtained in Production Example 1-1 (2.00 g, 7.96 mmol) was dissolved in dimethylformamide (40 ml), and sodium hydrogen carbonate (669 mg, 7.96 mmol) and water (10 ml) were added thereto and stirred.

[0103] (1,1'-bis(diphenylphosphino)ferrocene)palladium(II) chloride (0.796 mmol, 582.4 mg) and 2-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaboran-2-yl)isoindolin-1-one (2.61 g, 9.55 mmol) were added and stirred at 80-90°C for 1 hour. Upon completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (100 ml). The extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The residue was separated by silica gel column chromatography to obtain the following compound (1.40 g, 4.41 mmol).

[0104] 1 H-NMR (400MHz, DMSO-d6)δ 9.69(s, 1H), 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(t, 1H), 7.66(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 4.22(brs, 2H), 3.26(s, 3H) <Production Example 2> Production of 4-(2-(5-(chloromethyl)furan-2-yl)phenyl)-2-methylisoindolin-1-one

[0105] [ka] <Production Example 2-1> Production of 4-(2-(5-(hydroxymethyl)furan-2-yl)phenyl)-2-methylisoindolin-1-one 5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde (10.0 g, 31.5 mmol) synthesized in <Production Example 1> was added to and dissolved in absolute ethanol (100 ml), and the mixture was stirred while sodium borohydride (1.79 g, 47.2 mmol) was added dropwise at 0°C. After stirring at the same temperature for 1 hour, the reaction was confirmed to be complete, and then quenched with 10% sodium hydroxide solution.

[0106] The ethanol was concentrated under reduced pressure, and the residue was extracted three times with dichloromethane and water, and the extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. <Production Example 2-2: Production of 4-(2-(5-(chloromethyl)furan-2-yl)phenyl)-2-methylisoindolin-1-one> 4-(2-(5-(hydroxymethyl)furan-2-yl)phenyl)-2-methylisoindolin-1-one (7.0 g, 21.9 mmol) synthesized in Preparation Example 2-1 was dissolved in dichloromethane (100 ml), and thionyl chloride (2.38 ml, 32.8 mmol) was slowly added dropwise at 0°C, followed by stirring at the same temperature for 1 hour. Upon completion of the reaction, water (30 ml) was added to terminate the reaction, and the mixture was extracted three times with dichloromethane and water. The extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue.

[0107] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(t, 1H), 7.66(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 4.49(s, 2H), 4.22(brs, 2H), 3.27(s, 3H) <Production Example 3> Production of 3-methyl-5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde

[0108] [ka] 3-methyl-5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde was produced in the same manner as in Production Example 1 using 3-methyl-2-furancarboxaldehyde.

[0109] 1 H-NMR (400MHz, DMSO-d6)δ 9.68(s, 1H), 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(t, 1H), 7.60(d, 2H), 4.22(s, 2H), 3.27(s, 3H), 2.33(s, 3H)

[0110] [Example]

[0111] Example 1: Synthesis of 2-methyl-4-(2-(5-((methylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0112] [ka] 5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde (80 mg, 0.252 mmol) obtained in Preparation Example 1-2 was dissolved in dichloromethane (5 ml), and sodium triacetoxyborohydride (80.1 mg, 0.378 mmol), acetic acid (10 μl), and methylamine hydrochloride (25.5 mg, 0.378 mmol) were added sequentially, followed by stirring at room temperature for 12 hours. Upon completion of the reaction, water was added to the mixture, which was then extracted with dichloromethane (20 ml). The extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The residue was purified by silica gel column chromatography to obtain 2-methyl-4-(2-(5-((methylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one (16.3 mg, 0.478 mmol).

[0113] 1H-NMR (400MHz, DMSO-d6)δ 8.04(d, 1H), 7.97(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.66(d, 1H), 7.61(t, 1H), 7.32(d , 1H), 6.29(d, 1H), 4.16(m, 1H), 4.22(brs, 2H), 3.65(d, 2H), 3.27(s, 3H), 3.25(d, 3H) MS(ESI+)m / z 333(M+H) + Hereinafter, Examples 2 to 26 were synthesized by the same method as in Example 1, or were produced using appropriate reactants in consideration of the structure of the compound to be produced.

[0114] Example 2: Synthesis of 2-methyl-4-(2-(5-((ethylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0115] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.03(d, 1H), 7.95(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.16(m, 1H), 4.22(brs, 2H), 3.65(d, 2H), 3.27(s, 3H), 2.66(m, 2H), 1.12(t, 3H) MS(ESI+)m / z 347(M+H) +

[0116] Example 3: Synthesis of 2-methyl-4-(2-(5-((propylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0117] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.03(d, 1H), 7.95(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.22(brs, 2H), 4.16(m, 1H), 3.65(d, 2H), 3.27(s, 3H), 2.66(m, 2H), 1.12(t, 3H) MS(ESI+)m / z 361(M+H) +

[0118] Example 4: Synthesis of 2-methyl-4-(2-(5-((methoxymethylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0119] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.63(d, 2H), 4.16(m, 1H), 4.21(brs, 2H), 3.65(d, 2H), 3.30(s, 3H), 3.27(s, 3H) MS(ESI+)m / z 363(M+H) +

[0120] Example 5: Synthesis of 2-methyl-4-(2-(5-((dimethylaminoethylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0121] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.28(d , 1H), 4.22(brs, 2H), 4.16(m, 1H), 3.66(d, 2H), 3.27(s, 3H), 2.50(m, 2H), 2.39(d, 2H), 2.21(s, 6H) MS(ESI+)m / z 390(M+H) +

[0122] Example 6: Synthesis of 2-methyl-4-(2-(5-((methyl(prop-2-yn-1-yl)amino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0123] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.87(s, 2H), 3.76(s, 2H), 3.27(s, 3H), 3.08(s, 1H), 2.25(s, 3H) MS(ESI+)m / z 371(M+H) +

[0124] Example 7: Synthesis of 2-methyl-4-(2-(5-((cyclopentylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0125] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4 .22(brs, 2H), 4.16(brs, 1H), 3.66(d, 2H), 3.27(s, 3H), 2.64(m, 1H), 1.72-1.47(m, 4H), 1.73-1.63(m, 4H) MS(ESI+)m / z 387(M+H) +

[0126] Example 8: Synthesis of 2-methyl-4-(2-(5-((isopropylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0127] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6 .29(d, 1H), 4.22(brs, 2H), 4.15(brs, 1H), 3.65(d, 2H), 3.27(s, 3H), 2.83(m, 1H), 1.06(s, 6H) MS(ESI+)m / z 361(M+H) +

[0128] Example 9: Synthesis of 2-methyl-4-(2-(5-(((methylsulfonyl)ethyl)amino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0129] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6 .29(d, 1H), 4.22(brs, 2H), 4.15(brs, 1H), 3.65(d, 2H), 3.53(d, 2H), 3.27(s, 3H), 2.80(s, 3H) MS(ESI+)m / z 425(M+H) +

[0130] Example 10: Synthesis of 2-methyl-4-(2-(5-(((2-(4-methylpiperazin-1yl)ethyl)amino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0131] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.22(brs, 2H) , 4.16(brs, 1H), 3.65(d, 2H), 3.27(s, 3H), 2.50(m, 2H), 2.39(t, 2H), 2.27-2.29(m, 4H), 2.29-2.31(m, 4H), 2.14(s, 3H) MS(ESI+)m / z 445(M+H) +

[0132] Example 11: Synthesis of 2-methyl-4-(2-(5-((4-methylsulfonyl)piperazin-1-yl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0133] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(S, 2H), 3.27(s, 3H), 2.45(m, 4H), 2.34(m, 4H), 2.87(s, 3H) MS(ESI+)m / z 466(M+H) +

[0134] Example 12: Synthesis of 2-methyl-4-(2-(5-(piperidin-1-ylmethyl)furan-2-yl)phenyl)isoindolin-1-one

[0135] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29( d, 1H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 2.39-2.41(m, 4H), 1.43-1.42(m, 4H), 1.30(m, 2H) MS(ESI+)m / z 387(M+H) +

[0136] Example 13: Synthesis of 2-methyl-4-(2-(5-(morpholinomethyl)furan-2-yl)phenyl)isoindolin-1-one

[0137] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 3.50-3.52(m, 4H), 2.41-2.24(m, 4H) MS(ESI+)m / z 389(M+H) +

[0138] Example 14: Synthesis of 2-methyl-4-(2-(5-(((4-(3-fluorophenyl)piperazin-1-yl)methyl))furan-2-yl)phenyl)isoindolin-1-one

[0139] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 7.12(t, 1H), 6.83(s, 1H), 6.71(d, 1H), 6.44(d, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(d, 2H), 3.27(s, 3H), 3.20-3.25(m, 4H), 2.45-2.43(m, 4H) MS(ESI+)m / z 482(M+H) +

[0140] Example 15: Synthesis of 2-methyl-4-(2-(5-((4-(dimethylamino)piperidin-1-yl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0141] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 2.63(t, 1H), 2.51-2.49(m, 4H), 1.65-1.55(m, 4H), 2.26(S, 6H), MS(ESI+)m / z 431(M+H) +

[0142] Example 16: Synthesis of 2-methyl-4-(2-(5-(((4-(pivaloamidyl)piperazin-1yl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0143] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.32(d, 1H), 6.94 (brs, 2H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(d, 2H), 3.27(s, 3H), 2.32-2.20(m, 8H), 1.54(s, 6H) MS(ESI+)m / z 473(M+H) +

[0144] Example 17: Synthesis of 2-methyl-4-(2-(5-((benzylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0145] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.35(d, 2H), 7.32(m, 3H), 7.29(t, 1H), 6.29(d, 1H), 5.00(brs, 1H), 4.22(brs, 2H), 3.76(d, 2H), 3.66(d, 2H), 3.27(s, 3H) MS(ESI+)m / z 409(M+H) +

[0146] Example 18: Synthesis of 2-methyl-4-(2-(5-((((1-methyl-1H-pyrazol-4yl)methyl)amino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0147] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.47(s, 1H), 7.37(s, 1H), 7 .32(d, 1H), 6.29(d, 1H), 5.00(brs, 1H), 4.22(brs, 2H), 3.94(s, 3H), 3.76(d, 2H), 3.66(d, 2H), 3.27(s, 3H) MS(ESI+)m / z 413(M+H) +

[0148] Example 19: Synthesis of 2-methyl-4-(2-(5-((((4-benzyl-4'-methylcarboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0149] [ka] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.51(t, 1H), 7.32(d, 1H), 7.21(d, 2H), 7.23(m, 2) H), 7.19(m, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.71(s, 2H), 2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 534(M+H) +

[0150] Example 20: Synthesis of 2-methyl-4-(2-(5-((((4-(4-fluorobenzyl)-4'-benzylcarboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0151] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.87(t, 1H), 8.05(d, 1H), 7.96(d, 2H), 7.70(t, 1H), 7.65(d, 1H), 7.51(t, 1H), 7.23-7.30(m, 5H), 7.32(d, 1H), 7.21(d, 2H), 7.23(m, 2) H), 7.19(m, 1H), 6.29(d, 1H), 4.24(t, 2H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 2.71(s, 2H), 2.51-2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 628(M+H) +

[0152] Example 21: Synthesis of 2-methyl-4-(2-(5-(((4-(4-fluorobenzyl)-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0153] [ka]

[0154] [Step 1] Preparation of 4-(4-fluorobenzyl)-N-methylpiperidine-4-carboxamide hydrochloride

[0155] [ka] 1-(tert-Butoxycarbonyl)-4-(4-fluorobenzyl)piperidine-4-carboxylic acid (5.0 g, 14.8 mmol) was dissolved in anhydrous dimethylformamide, and HBTU (N,N,N',N'-tetramethyl-O-(1H-benzotriazol-1-yl)uronium hexafluorophosphate 8.42 g, 22.2 mmol) and N-diethyl-N-isopropylamine (48.8 mmol) were added and stirred at room temperature for 30 minutes. Methylamine hydrochloride (59.2 mmol) was added to the reaction mixture, and the mixture was stirred at 70°C for 12 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (200 mL). The extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The residue was dissolved in 1N aqueous HCl (100 mL) and stirred at 40°C for 4 hours. Upon completion of the reaction, the mixture was cooled to room temperature, water was added, and the mixture was extracted with ethyl acetate (200 ml, twice). The extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue. The product was separated by silica gel column chromatography to obtain 4-(4-fluorobenzyl)-N-methylpiperidine-4-carboxamide hydrochloride (3.40 g, 11.8 mmol).

[0156] [Step 2] Synthesis of 2-methyl-4-(2-(5-(((4-(4-fluorobenzyl)-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one Using 4-(4-fluorobenzyl)-N-methylpiperidine-4-carboxamide hydrochloride prepared in [Step 1] above and 5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde prepared in Preparation Example 1-2, 2-methyl-4-(2-(5-(((4-(4-fluorobenzyl)-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one compound was synthesized in the same manner as in Example 1.

[0157] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.60(m, 2H), 7.51(t, 1H), 7.18(d, 2H), 7.16(d, 2H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.71(s, 2H), 2.51-2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 552(M+H) +

[0158] Example 22: Synthesis of 2-methyl-4-(2-(5-((4-(4-fluorophenyl)-2λ2,8-diazaspiro[4,5]decan-1-one)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0159] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.60(m, 2H), 7.50(t, 1H), 7.18(d, 2H), 7.16(d, 2H), 6.29(d, 1H), 4.22( brs, 2H), 3.81(m, 2H), 3.76(s, 2H), 3.27(s, 3H), 3.18(d, 2H), 2.71(s, 2H), 2.51-2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 549(M+H) +

[0160] Example 23: Synthesis of 2-methyl-4-(2-(5-(((4-(4-fluorophenyl)-2-methyl)-2λ2,8-diazaspiro[4,5]decan-1-one)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0161] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.98(d, 2H), 7.94(d, 1H), 7.60(m, 2H), 7.50(t, 1H), 7.18(d, 2H), 7.16(d, 2H), 6.29(d, 1H), 4.22(brs, 2H) ), 3.81(m, 2H), 3.76(s, 2H), 3.27(s, 3H), 3.19(d, 2H), 2.94(s, 3H), 2.71(s, 2H), 2.51-2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 564(M+H) +

[0162] Example 24: Synthesis of 2-methyl-4-(2-(5-((3-ethyl-3'-N-methyl-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0163] [ka]

[0164] [Step 1] Preparation of 3-ethyl-N-methylpiperidine-3-carboxamide hydrochloride

[0165] [ka] 3-Ethyl-N-methylpiperidine-3-carboxamide hydrochloride compound was prepared in the same manner as in Example 23 [Step 1] using 1-(tert-butoxycarbonyl)-3-ethylpiperidine-3-carboxylic acid.

[0166] [Step 2] Synthesis of 2-methyl-4-(2-(5-((3-ethyl-3'-N-methyl-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0167] Using 3-ethyl-N-methylpiperidine-3-carboxamide hydrochloride prepared in [Step 1] and 5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde prepared in Preparation Example 1-2, 2-methyl-4-(2-(5-((3-ethyl-3'-N-methyl-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one compound was synthesized in the same manner as in Example 1.

[0168] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(t, 1H), 6.29(d, 1H), 4.22(brs, 2H) ), 3.47(s, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.48-2.40(m, 4H), 1.53-1.43(m, 4H), 1.49(m, 2H), 0.89(t, 3H), MS(ESI+)m / z 472(M+H) +

[0169] Example 25: Synthesis of 2-methyl-4-(2-(5-(((4-hydroxy)3-methyl-3'-N-methyl-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0170] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.48(t, 1H), 6.77(d, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.80(m, 1H), 3.47(s, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.65-2.59(m, 2H), 2.51-2.41(m, 2H), 1.77-1.52(m, 2H), 1.32(s, 3H) MS(ESI+)m / z 474(M+H) +

[0171] Example 26: Synthesis of 2-methyl-4-(2-(5-((N-methyl-2-(3-oxopiperazin-2yl)acetamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0172] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(d, 1H), 7.52(t, 1H), 6.97(d, 1H), 6.29(d, 1H) ), 4.22(brs, 2H), 3.87(d, 1H), 3.47(s, 2H), 3.31(m, 2H), 3.27(s, 3H), 2.92-2.87(m, 2H), 2.80(s, 3H), 2.65(d, 2H), MS(ESI+)m / z 473(M+H) +

[0173] Example 27: Synthesis of 2-methyl-4-(2-(5-((3-benzyl-N-methylpiperidine-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0174] [ka] 3-Benzyl-N-methylpiperidine-3-carboxamide (1.0 g, 4.30 mmol) was dissolved in acetonitrile (50 ml), and potassium carbonate (891 mg, 6.45 mmol) and potassium iodide (71.38 mg, 0.43 mmol) were added. 4-(2-(5-(chloromethyl)furan-2-yl)phenyl)-2-methylisoindolin-1-one (1.45 g, 4.30 mmol) synthesized in Preparation Example 2-2 was added to the reaction solution, and the mixture was stirred at room temperature for 7 hours. Upon completion of the reaction, the mixture was extracted with dichloromethane (150 ml) and water (150 ml), and the separated organic layer was concentrated under reduced pressure using anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography to obtain 2-methyl-4-(2-(5-((3-benzyl-N-methylpiperidine-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one compound.

[0175] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(m, 1H), 7.23(m, 2H), 7.21(d, 2H), 7.19(d, 1H), 4.22( brs, 2H), 3.47(s, 2H), 3.27(s, 3H), 2.84(s, 2H), 2.80(d, 3H), 2.65(s, 2H), 2.48(d, 2H), 1.80-1.72(m, 2H), 1.53-1.50(m, 2H) MS(ESI+)m / z 534(M+H) +

[0176] Example 28: Synthesis of 2-methyl-4-(2-(5-((3-benzyl-N-methylpiperidine-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0177] [ka] Using 2-benzyl-N-methylpyrrolidine-2-carboxamide, 2-methyl-4-(2-(5-((3-benzyl-N-methylpiperidine-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 27.

[0178] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(m, 1H), 7.23(m, 2H), 7.21(d, 2H), 7.19(d , 1H), 4.22(brs, 2H), 3.47(s, 2H), 3.27(s, 3H), 2.96(s, 2H), 2.82(d, 3H), 2.40(d, 2H), 1.90(d, 2H), 1.64(m, 2H) MS(ESI+)m / z 521(M+H) +

[0179] Example 29: Synthesis of 2-methyl-4-(2-(5-(((4-benzyl-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0180] [ka] Using 4-(benzyl)-4-piperidine-carboxamide, 2-methyl-4-(2-(5-(((4-benzyl-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 27.

[0181] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.65(d, 1H), 7.61(t, 1H), 7.50(t, 1H), 7.32(d, 1H), 7.21(d, 2H), 7.23(m, 2H) ), 7.19(m, 1H), 7.12(brs, 2H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 2.71(s, 2H), 2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 521(M+H) +

[0182] Example 30: Synthesis of 2-methyl-4-(2-(5-((3-benzyl-N-methylpiperidine-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0183] [ka]

[0184] Using (3S)-N-cyclopropyl-3-(benzyl)-3-piperidinecarboxamide, 2-methyl-4-(2-(5-((3-benzyl-N-methylpiperidine-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one was obtained in the same manner as in Example 27.

[0185] 1H-NMR (400 MHz, DMSO-d6) δ 8.20(brs, 1H), 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60 (m, 2H), 7.50 (m, 1H), 7.23 (m, 2H), 7.21 (d, 2H), 7.19 (d, 1H), 4.22 (brs, 2) H), 3.47(s, 2H), 3.27(s, 3H), 2.84(s, 2H), 2.69(m, 1H), 2.65(s, 2H), 2.4 8(d, 2H), 1.80-1.72(m, 2H), 1.53-1.50(m, 2H), 0.82(m, 2H), 0.57(m, 2H) MS(ESI+)m / z 560(M+H) +

[0186] Example 31: Synthesis of 2-methyl-4-(2-(5-(((4-pyridinylmethyl-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0187] [ka] Using 4-(4-pyridinylmethyl)-4-piperidine-carboxamide, 2-methyl-4-(2-(5-(((4-pyridinylmethyl-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 27.

[0188] 1 H-NMR (400MHz, DMSO-d6)δ 8.55(d, 2H), 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.69(d, 1H), 7.23(d, 2H), 7.10(brs, 2H), 6.29(d, 1H), 4.22(brs, 2H), 3.76(s, 2H), 3.27(s, 3H), 2.71(s, 2H), 2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 521(M+H) +

[0189] Example 32: Synthesis of 2-methyl-4-(2-(5-(((4-(4-fluorobenzyl)-4'-carboxyamidyl)piperidine)carbonyl)furan-2-yl)phenyl)isoindolin-1-one

[0190] [ka] 5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde (1.0 g, 3.15 mmol) synthesized in Preparation 1 was dissolved in acetonitrile (50 mL), and cobalt(II) iodide (24.6 mg, 0.078 mmol), calcium carbonate (346 mg, 3.47 mmol), tert-butyl hydroperoxide (70% in HO, 1.51 mL, 11.0 mmol), and 4-(4-fluorobenzyl)-N-methylpiperidine-4-carboxamide hydrochloride (3.47 mmol) prepared in Step 1 of Example 20 were added under a nitrogen atmosphere and stirred. The reaction mixture was stirred at 70°C for 24 hours. Upon completion of the reaction, the mixture was cooled to room temperature, and saturated aqueous ammonium chloride solution (30 mL) was added and stirred. Water was added, and the mixture was extracted with ethyl acetate (200 mL, twice). The extracted solution was dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain a residue, which was separated by silica gel column chromatography to obtain 2-methyl-4-(2-(5-(((4-(4-fluorobenzyl)-4'-carboxyamidyl)piperidine)carbonyl)furan-2-yl)phenyl)isoindolin-1-one compound.

[0191] 1 H-NMR (400MHz, DMSO-d6)δ 8.06(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.60(m, 2H), 7.50(t, 1H), 7.21(d, 1H), 7.18(d, 2H), 7.13( d, 2H), 4.22(brs, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.71(s, 2H), 2.51-2.45(m, 4H), 1.80-1.67(m, 4H) MS(ESI+)m / z 566(M+H) +

[0192] Example 33: Synthesis of 2-methyl-4-(2-(5-((methylamino)carbonyl)furan-2-yl)phenyl)isoindolin-1-one

[0193] [ka] Using methylamine hydrochloride, 2-methyl-4-(2-(5-((methylamino)carbonyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 32.

[0194] 1 H-NMR (400MHz, DMSO-d6)δ 8.04(d, 1H), 7.97(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.66(d, 1H), 7.61(t, 1H), 7.56(d, 1H), 7.21(d, 1H), 7.13(d, 1H), 4.22(brs, 2H), 3.27(s, 3H), 2.85(d, 3H) MS(ESI+)m / z 347(M+H) +

[0195] Example 34: Synthesis of 2-methyl-4-(2-(5-(((4-hydroxy)3-methyl-3'-N-methyl-carboxyamidyl)piperidine)carbonyl)furan-2-yl)phenyl)isoindolin-1-one

[0196] [ka] Using 4-hydroxy-3-methyl-3'-N-methyl-carboxyamidyl-piperidine, 2-methyl-4-(2-(5-(((4-hydroxy)3-methyl-3'-N-methyl-carboxyamidyl)piperidine)carbonyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 32.

[0197] 1H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.48(t, 1H), 7.21(d, 1H), 7.13(d, 1H), 6.77(d, 1H), 4. 22(brs, 2H), 3.80(m, 1H), 3.27(s, 3H), 2.80(d, 3H), 2.65-2.59(m, 2H), 3.59-3.49(m, 2H), 1.93-1.68(m, 2H), 1.32(s, 3H) MS(ESI+)m / z 488(M+H) +

[0198] Example 35: Synthesis of 2-methyl-4-(2-(5-((N-methyl-2-(3-oxopiperazin-2yl)acetamidyl)carbonyl)furan-2-yl)phenyl)isoindolin-1-one

[0199] [ka] Using N-methyl-2-(3-oxopiperazin-2yl)acetamidyl, 2-methyl-4-(2-(5-((N-methyl-2-(3-oxopiperazin-2yl)acetamidyl)carbonyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 32.

[0200] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(d, 1H), 7.52(t, 1H), 7.21(d, 1H), 7.13( d, 1H), 4.84(m, 1H), 4.22(brs, 2H), 3.47(s, 2H), 3.31-3.28(m, 2H), 3.27(s, 3H), 3.01-2.80(m, 2H), 2.80(d, 3H) MS(ESI+)m / z 487(M+H) +

[0201] Example 36: Synthesis of 2-methyl-4-(2-(5-((3-ethyl-3'-N-methyl-carboxyamidyl)piperidine)carbonyl)furan-2-yl)phenyl)isoindolin-1-one

[0202] [ka] Using 3-ethyl-3'-N-methyl-carboxyamidyl)piperidine, 2-methyl-4-(2-(5-((3-ethyl-3'-N-methyl-carboxyamidyl)piperidine)carbonyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 32.

[0203] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(t, 1H), 7.13(d, 1H), 4.22(b rs, 2H), 3.56-3.52(m, 4H), 3.27(s, 3H), 2.80(d, 3H), 1.68-1.58(m, 4H), 1.48(m, 2H), 0.89(t, 3H), MS(ESI+)m / z 486(M+H) +

[0204] Example 37: Synthesis of 2-methyl-4-(2-(5-((((4,4-difluoropiperidin-1-yl)methoxy)-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0205] [ka] 4,4-Difluoropiperidin-1-yl)methanol (0.53 g, 3.50 mmol) was dissolved in dimethylformamide (20 ml), and sodium hydride (60%, 154 mg, 3.85 mmol) was slowly added dropwise at 0°C. The mixture was stirred at the same temperature for 1 hour, and then 4-(2-(5-(chloromethyl)furan-2-yl)phenyl)-2-methylisoindolin-1-one (1.29 g, 3.85 mmol) synthesized in Preparation Example 2-2 was slowly added dropwise, followed by stirring at room temperature for 4 hours. Upon completion of the reaction, the mixture was extracted with ethyl acetate (150 ml) and water (150 ml, twice), and the separated organic layer was concentrated under reduced pressure using anhydrous magnesium sulfate. The residue was purified by silica gel column chromatography to obtain 2-methyl-4-(2-(5-((((4,4-difluoropiperidin-1-yl)methoxy)-3-carboxyamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one compound.

[0206] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 6.98(d, 1H), 6.59(d , 1H), 4.48(s, 2H), 4.44(s, 2H), 4.22(brs, 2H), 3.27(s, 3H), 2.45(m, 4H), 1.82(m, 4H) MS(ESI+)m / z 453(M+H) + The following Examples 38 to 42 were synthesized using 3-methyl-5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde obtained in <Preparation Example 3> in the same manner as in Example 1, or were prepared using appropriate reactants in consideration of the structure of the compound to be prepared.

[0207] Example 38: Synthesis of 2-methyl-4-(2-(3-methyl-5-((methylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0208] [ka] Using 3-methyl-5-(2-(2-methyl-1-oxoisoindolin-4-yl)phenyl)furan-2-carbaldehyde synthesized in <Production Example 3> and methylamine hydrochloride, a 2-methyl-4-(2-(3-methyl-5-((methylamino)methyl)furan-2-yl)phenyl)isoindolin-1-one compound was obtained in the same manner as in Example 1.

[0209] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.97(d, 2H), 7.94(d, 1H), 7.70(t, 1H), 7.66(d, 1H), 7.61(t, 1H), 6.33(d , 1H), 4.16(m, 1H), 4.22(brs, 2H), 3.65(d, 2H), 3.27(s, 3H), 3.25(d, 3H), 2.01(s, 3H) MS(ESI+)m / z 347(M+H) +

[0210] Example 39: Synthesis of 2-methyl-4-(2-(5-((3-methyl(4-(4-fluorobenzyl)-4'-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0211] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.60(m, 2H), 7.51(t, 1H), 7.18(d, 2H), 6.33(d, 1H), 4.22(brs, 2H) ), 3.76(s, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.71(s, 2H), 2.51-2.45(m, 4H), 2.01(s, 3H), 1.80-1.67(m, 4H) MS(ESI+)m / z 566(M+H) +

[0212] Example 40: Synthesis of 2-methyl-4-(2-(5-(3-methyl(3-ethyl-3'-N-methyl-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0213] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(t, 1H), 6.29(d, 1H), 4.22(brs, 2H), 3.47 (s, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.48-2.40(m, 4H), 2.01(s, 3H), 1.53-1.43(m, 4H), 1.49(m, 2H), 0.89(t, 3H), MS(ESI+)m / z 486(M+H) +

[0214] Example 41: Synthesis of 2-methyl-4-(2-(5-((3-methyl(4-hydroxy)3-methyl-3'-N-methyl-carboxyamidyl)piperidine)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0215] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.48(t, 1H), 6.33(d, 1H), 4.22(brs, 2H), 3.80(m, 1H), 3.47(s, 2H), 3.27(s, 3H), 2.80(d, 3H), 2.65-2.59(m, 2H), 2.51-2.41(m, 2H), 2.01(s, 3H), 1.77-1.52(m, 2H), 1.32(s, 3H) MS(ESI+)m / z 488(M+H) +

[0216] Example 42: Synthesis of 2-methyl-4-(2-(5-(3-methyl(N-methyl-2-(3-oxopiperazin-2yl)acetamidyl)methyl)furan-2-yl)phenyl)isoindolin-1-one

[0217] [ka] 1 H-NMR (400MHz, DMSO-d6)δ 8.05(d, 1H), 7.96(d, 2H), 7.94(d, 1H), 7.69(m, 1H), 7.60(m, 2H), 7.50(d, 1H), 7.52(t, 1H), 6.33(d, 1H), 4.22(brs , 2H), 3.87(d, 1H), 3.47(s, 2H), 3.31(m, 2H), 3.27(s, 3H), 2.92-2.87(m, 2H), 2.80(s, 3H), 2.65(d, 2H), 2.01(s, 3H) MS(ESI+)m / z 487(M+H) +

[0218] [Comparative Example] The compounds of Comparative Examples 1 to 3 in Table 8 below were prepared and subjected to an experiment on the BRD inhibitory effect.

[0219] [Table 8] [Test Example 1]

[0220] [Evaluation of the efficacy of inhibiting binding to BRD protein] To evaluate the ability of the novel compounds of the present invention to inhibit the interaction between the bromodomains of BRD2 (BD1) and BRD3 (BD1), which are members of the BRD protein family, and tetraacetylated histone H4 peptides, the following experiment was performed. 1-1. BRD2 protein binding inhibitory effect The binding inhibitory effect of the compounds of the present invention and the comparative compounds on BRD2 protein, one of the BRD proteins, was tested as follows.

[0221] Compounds were diluted in assay buffer from 10 mM stocks in DMSO (100 μM starting concentration) in 1:5 serial dilutions in white OptiPlate-384 (PerkinElmer). A mixture consisting of 100 nM GST-BRD2 (BD1) and 100 nM biotinylated acetyl-histone H4 (Lys5, 8, 12, 16) peptide was prepared in assay buffer (50 mM HEPES pH 7.4; 25 mM NaCl; 0.05% Tween 20; 0.1% bovine serum albumin (BSA); 10 mM dithiothreitol (DTT)). Six microliters of the mixture was added to the dilutions, followed by 6 μl of premixed AlphaLISA Glutathione Acceptor Beads (PerkinElmer) and AlphaScreen Streptavidin Donor Beads (PerkinElmer) at 10 μg / ml each in assay buffer. The samples were incubated in the dark at room temperature for 30 minutes with shaking at 300 rpm. Signals were then measured using the PerkinElmer Envision HTS Multilabel Reader using the PerkinElmer AlphaScreen protocol. Each plate contained negative controls in which biotinylated acetyl-histone H4 peptide and GST-BRD2 (BD1) were removed and replaced with assay buffer.

[0222] When using the software GraphPad Prism for calculation, the negative control value was entered as a low reference value. A positive control (probe molecule I-BET762 with a protein / peptide mixture) was also pipetted. The IC50 values ​​were determined using GraphPad Prism 3.03 software (or its updated version), and the results are shown in Table 9 below.

[0223] [Table 9] As shown in Table 9, the compounds of the present invention had lower IC50 values ​​for BRD2 (BD1) than the comparative compounds. Therefore, it was confirmed that the compounds of the present invention have superior inhibitory activity against BRD2 (BD1) protein compared to existing BRD inhibitors. 1-2. BRD3 protein binding inhibitory effect An experiment was carried out in the same manner as in Test Example 1-1 to confirm the inhibitory effect of the compounds of the present invention and the comparative compounds on the binding of BRD3 (BD1) protein. The results are shown in Table 10 below.

[0224] [Table 10] As shown in Table 10, the compounds of the present invention had much lower IC50 values ​​for BRD3 (BD1) than the comparative compounds. Therefore, it was confirmed that the compounds of the present invention have a more potent inhibitory effect on BRD3 (BD1) protein than the existing BRD inhibitor (RVX-208).

[0225] [Test Example 2]

[0226] [Evaluation of the efficacy of retinal degeneration inhibitors in a mouse model of retinal degeneration] Seven-week-old male albino BALB / c mice were used to create the retinal degeneration model. Three mice were randomly assigned to each experimental group and maintained under a 12-hour light / dark cycle. After 24 hours of dark adaptation, each mouse's pupils were dilated with 0.5% tropicamide and 0.5% phenylephrine hydrochloride eye drops (Santen, Osaka, Japan) 30 minutes before exposure to blue LED. Unanesthetized mice were exposed to 2,000 lux of blue LED (460 ± 10 nm) for 2 hours in a cage with reflective interiors. Light intensity was measured using an LED photometer (Model TM-201L, TENMARS Electronics, Taipei, Taiwan). After blue LED exposure, the mice were placed in 24 hours of darkness and then resumed with a 12-hour light / dark cycle for 3 days.

[0227] For the test substance control test, mice with retinal degeneration were randomly assigned to a saline (normal saline) group and a compound of the present invention (24 nM) group, with three mice assigned to each group.For the positive control test, mice were randomly assigned to a saline group and an Eyela (25 mg / kg mouse body weight) group (Comparative Example 4), with three mice assigned to each group.

[0228] All test groups were administered as a single intravitreal injection 1 hour after LED exposure.

[0229] [Electroretinography (ERG)] Electroretinography (ERG) recordings were performed according to the experimental procedure described by Kim et al. (Kim, GH, Kim, HI, Paik, SS, Jung, SW, Kang, S., and Kim, IB (2016). Functional and morphological evaluation of blue light-emitting diode-induced retinal degeneration in mice. Graefes Arch. Clin. Exp. Ophthalmol. 254, 705-716).

[0230] Mice were kept in a completely dark room for 16 hours before ERG recording. All animals were anesthetized intraperitoneally with zolazepam (20 mg / kg) and xylazine (7.5 mg / kg). The cornea was coated with hydroxypropyl methylcellulose gel and covered with a gold contact electrode. Ground and reference electrodes were placed subcutaneously on the tail and ear, respectively. Stimuli were brief white flashes delivered via a Ganzfeld stimulator (UTAS-3000; LKC Technologies, Gaithersburg, MD, USA). The signals were amplified and filtered through a digital bandpass filter in the 5–300 Hz range to generate a- and b-waves. Scotopic ERG, rod-mediated responses, were measured at 0.025 and 3.96 cd / s m. 2 Photopic, cone-mediated responses were obtained after 5 minutes of light adaptation to background luminosity. Recordings were made at a luminosity of 6.28 cd / s m 2 Each recording was the average of three responses obtained within a 15-second interstimulus interval. The amplitude of the a-wave was measured from baseline to the maximum a-wave peak, and the b-wave was measured from the maximum a-wave peak to the maximum b-wave peak.

[0231] The results of the ERG analysis are presented in Table 11 below.

[0232] [Table 11] As shown in Table 11, when the wavelength increase compared to the saline treatment group was expressed as a fold increase, the group treated with the compound of the present invention showed a superior increase in wavelength compared to the group treated with Eyela, a commercially available macular degeneration treatment. Therefore, it was confirmed that the compound of the present invention exhibits a superior retinal degeneration inhibitory effect than the existing macular degeneration treatment, Eyela.

[0233] [Test Example 3]

[0234] [Evaluation of efficacy in preventing macular degeneration in a mouse model of macular degeneration] Mice were subjected to general anesthesia, and then anesthetic eye drops were instilled into the eyes to induce additional local anesthesia, followed by mydriasis induction. Following the macular degeneration induction conditions, laser burn was induced and Bruch's membrane was destroyed to prepare animal macular degeneration models. The test substances (compounds 1–42; 0.022 μg / eye), the control substance (comparison example 4; aflibercept (Eylea); 20 μg / eye), and the negative control substance (vehicle) were administered bilaterally at a volume of 1 μL / eye via scleral puncture with a 36G needle immediately after macular degeneration induction. On day 11 after macular degeneration induction, mice were subjected to general anesthesia and intraperitoneal injection of a fluorescent contrast agent. The mice were placed on a platform, and lubricating gel was instilled into the eyes. An OCT lens was then placed in contact with the mouse cornea. Image analysis for fluorescein fundus angiography (FFA) and OCT was performed using the Image-J program.

[0235] The analysis results obtained through the OCT imaging are shown in Table 12 and FIGS. 1 to 3 below.

[0236] [Table 12] As shown in Table 12 and Figures 1 to 3, analysis of changes in macular degeneration lesions showed that the group treated with the compound of the present invention had a statistically significant reduction in the size of macular degeneration lesions compared to the negative control group. The volume of macular degeneration lesions also decreased more in the group treated with the compound of the present invention than in the group treated with the control substance, Eylea.

[0237] The results of the analysis through the FFA imaging are shown in Table 13 and FIGS. 4 to 6 below.

[0238] [Table 13] As shown in Table 13 and Figures 4 to 6, analysis of changes in macular degeneration lesions showed a statistically significant reduction in the size of macular degeneration lesions in the group administered with the compound of the present invention compared to the negative control group. Additionally, a statistically significant greater reduction in CTF values ​​was observed in the group administered with the compound of the present invention compared to the group administered with the control substance, Eylea.

[0239] Therefore, it was confirmed that the compound of the present invention exhibits a more effective inhibitory effect on macular degeneration than the existing therapeutic agent for macular degeneration (Ira).

Claims

1. A compound of formula (I) below, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof: 【Chemical 1】 In the above formula, A and B are each independently any one selected from the group consisting of oxygen, nitrogen, and sulfur, and when at least one of A and B is nitrogen, a hydrogen atom bonded to the nitrogen atom is substituted with an alkyl group; C is hydrogen, C １－６ is any one selected from the group consisting of alkyl and carbonyl, D is hydrogen, C １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), -NH(C ３－６ cycloalkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl.

2. -NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), -NH(C ３－６ The hydrogen-bonding portions of cycloalkyl, cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are hydrogen, halogen, —OH, ═O, —OC １－６ Alkyl, —C １－６ Alkyl, —C(═O)Ra, —C(═O)N(Ra)(Rb), —C １－６ AlkylC(=O)N(Ra)(Rb), -C ３ H ４ C(=O)N(Ra)(Rb), -C≡CH, -C ３－６ Cycloalkyl, —N(C １－６ alkyl) (C １－６ alkyl), -SO ２ (C １－６ alkyl), phenyl, phenyl in which one or more of hydrogen or carbon is substituted with halogen, methylpiperazinyl, １－６ optionally substituted with one or more substituents selected from the group consisting of alkyl-substituted pyrazoyl, pyrrolidonyl in which any one of the hydrogen atoms is substituted with a halogenated phenyl, methylpyrrolidonyl in which any one of the hydrogen atoms is substituted with a halogenated phenyl, benzyl, benzyl in which any one or more of the hydrogen atoms or carbon atoms is substituted with nitrogen, and benzyl in which any one or more of the hydrogen atoms or carbon atoms is substituted with a halogen; The Ra and Rb each independently represent H, C １－６ Alkyl, C ３－６ 2. The compound of formula (I) of claim 1, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein R is cycloalkyl, cycloalkyl, or benzyl.

3. The compound of formula (I) according to claim 2, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, wherein the heterocycloalkyl of D comprises one or more selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, and piperazinonyl.

4. 3. The compound of formula (I), solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to claim 2, wherein C is either methyl or carbonyl.

5. A compound of formula (II) below, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof: 【Chemistry 2】 In the above formula, A and B are each independently any one selected from the group consisting of oxygen, nitrogen, and sulfur, and when at least one of A and B is nitrogen, a hydrogen bonded to the nitrogen is substituted with an alkyl group; C is hydrogen or C １－６ is alkyl, D is hydrogen, C １－６ Alkyl, —NH ２ , —NH(C １－６ alkyl), -N(C １－６ alkyl) (C １－６ alkyl), cycloalkyl, heterocycloalkyl, aryl, or heteroaryl; The cycloalkyl, heterocycloalkyl, aryl, and heteroaryl are selected from the group consisting of hydrogen, —OH, ═O, —C １－６ Alkyl, —C(═O)Ra, —C(═O)N(Ra)(Rb), —C １－６ It may be substituted with one or more substituents selected from the group consisting of alkylC(=O)N(Ra)(Rb) and benzyl in which one or more of hydrogen or carbon is substituted with halogen; The heterocycloalkyl includes one or more selected from the group consisting of pyrrolidinyl, piperidinyl, piperazinyl, methylpiperazinyl, morpholinyl, and piperazinonyl; The Ra and Rb each independently represent H or C. １－６ It is alkyl.

6. 6. The compound of formula (II), a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof according to claim 5, wherein C is methyl.

7. 10. The compound of formula (I) of claim 1, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds represented by the following chemical formula: 【Table 1】 【Table 2】 【Table 3】 【Table 4】 【Table 5】 【Table 6】

8. 6. The compound of formula (II) of claim 5, a solvate, a stereoisomer, or a pharmaceutically acceptable salt thereof, selected from the group consisting of compounds represented by the following chemical formula: 【Table 7】

9. A pharmaceutical composition for preventing or treating an ophthalmic disease, comprising the compound, solvate, stereoisomer, or pharmaceutically acceptable salt thereof according to any one of claims 1 to 8 as an active ingredient.

10. 10. The pharmaceutical composition for preventing or treating an ophthalmological disease according to claim 9, wherein the ophthalmological disease is endophthalmitis, keratitis, conjunctivitis, keratoconjunctivitis, uveitis, blepharitis, scleritis, iritis, glaucoma, retinal degeneration, retinitis pigmentosa, retinal detachment, retinal pigment epithelial detachment, retinal break, diabetic retinopathy, retinopathy of prematurity, polypoidal choroidal vasculopathy, ischemic proliferative retinopathy, cone dystrophy, proliferative vitreoretinopathy, retinal artery occlusion, retinal vein occlusion, Leber's hereditary optic neuropathy, corneal neovascularization, retinal and choroidal neovascularization, wet and dry macular degeneration, or age-related macular degeneration.

11. The pharmaceutical composition for preventing or treating an ophthalmic disease according to claim 9, wherein the ophthalmic disease is diabetic retinopathy, glaucoma, uveitis, wet and dry macular degeneration, or age-related macular degeneration.

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